The New England Journal of Medicine

Original Article
Volume 346:653-661

February 28, 2002

Number 9
Intravenous Zoledronic Acid in Postmenopausal Women with Low Bone Mineral
Density
Ian R. Reid, M.D., Jacques P. Brown, M.D., Peter Burckhardt, M.D., Zebulun
Horowitz, M.D., Peter Richardson, M.R.C.P., Ulrich Trechsel, M.D., Albert
Widmer, Dipl.Stat., Jean-Pierre Devogelaer, M.D., Jean-Marc Kaufman, M.D.,
Ph.D., Philippe Jaeger, M.D., Jean-Jacques Body, M.D., Ph.D., Maria Luisa
Brandi, M.D., Johann Broell, M.D., Raffaele Di Micco, M.D., Andrea Riccardo
Genazzani, M.D., Dieter Felsenberg, M.D., Joachim Happ, M.D., Michael J.
Hooper, F.R.A.C.P., Jochen Ittner, M.D., Georg Leb, M.D., Hans Mallmin,
M.D., Ph.D, Timothy Murray, M.D., Sergio Ortolani, M.D., Alessandro
Rubinacci, M.D., Maria Sääf, M.D., Ph.D., Goran Samsioe, M.D., Ph.D., Leon
Verbruggen, M.D., Ph.D., and Pierre J. Meunier, M.D.
ABSTRACT
Background Bisphosphonates are effective agents for the management of
osteoporosis. Their low bioavailability and low potency necessitate frequent
administration on an empty stomach, which may reduce compliance.
Gastrointestinal intolerance limits maximal dosing. Although intermittent
intravenous treatments have been used, the optimal doses and dosing interval
have not been systematically explored.
Methods We studied the effects of five regimens of zoledronic acid, the most
potent bisphosphonate, on bone turnover and density in 351 postmenopausal
women with low bone mineral density in a one-year, randomized, double-blind,
placebo-controlled trial. Women received placebo or intravenous zoledronic
acid in doses of 0.25 mg, 0.5 mg, or 1 mg at three-month intervals. In
addition, one group received a total annual dose of 4 mg as a single dose,
and another received two doses of 2 mg each, six months apart. Lumbar-spine
bone mineral density was the primary end point.
Results There were similar increases in bone mineral density in all the
zoledronic acid groups to values for the spine that were 4.3 to 5.1 percent
higher than those in the placebo group (P<0.001) and values for the femoral
neck that were 3.1 to 3.5 percent higher than those in the placebo group
(P<0.001). Biochemical markers of bone resorption were significantly
suppressed throughout the study in all zoledronic acid groups. Myalgia and
pyrexia occurred more commonly in the zoledronic acid groups, but
treatment-related dropout rates were similar to that in the placebo group.
Conclusions Zoledronic acid infusions given at intervals of up to one year
produce effects on bone turnover and bone density as great as those achieved
with daily oral dosing with bisphosphonates with proven efficacy against
fractures, suggesting that an annual infusion of zoledronic acid might be an
effective treatment for postmenopausal osteoporosis.
  _____

Oral bisphosphonates are widely used for treating osteoporosis and have been
shown to increase bone mineral density and decrease the rate of fracture. 1
<http://content.nejm.org/cgi/content/full/346/9/#R1> , 2
<http://content.nejm.org/cgi/content/full/346/9/#R2>  However, they do have
limitations related to long-term compliance, gastrointestinal intolerance,
and poor and variable absorption from the gastrointestinal tract.
Intermittent intravenous administration of bisphosphonates might address
some of these problems and has been shown to be effective in the treatment
of malignant hypercalcemia and Paget's disease and to reduce the rate of
skeletal complications in patients with breast carcinoma or multiple
myeloma. Evidence suggests that intravenous bisphosphonates increase bone
mineral density in patients with osteoporosis, but most relevant studies
have been small, unblinded, and short-term and have not systematically
examined the effects of the dose and dosing interval on changes in bone
mineral density and markers of bone turnover. 3
<http://content.nejm.org/cgi/content/full/346/9/#R3> , 4
<http://content.nejm.org/cgi/content/full/346/9/#R4> , 5
<http://content.nejm.org/cgi/content/full/346/9/#R5> , 6
<http://content.nejm.org/cgi/content/full/346/9/#R6>
Zoledronic acid is the most potent bisphosphonate that has been studied in
clinical trials to date. 7
<http://content.nejm.org/cgi/content/full/346/9/#R7>  It is superior to
pamidronate in the treatment of cancer-related hypercalcemia. 8
<http://content.nejm.org/cgi/content/full/346/9/#R8>  Because it has high
potency, only small doses are required for the inhibition of bone
resorption, and long dosing intervals may be used. We undertook a phase 2
study to examine the effect of intravenous zoledronic acid on bone density
and bone turnover in postmenopausal women with low bone density and to
assess the effects of varying the total dose administered and the dosing
interval.
Methods
Study Subjects
A total of 351 postmenopausal women 45 to 80 years of age were studied at 24
centers in 10 countries. In all the women, menopause had occurred at least
five years previously, either naturally or as the result of bilateral
oophorectomy. All women had a bone mineral density at the lumbar spine (L1
to L4) that was at least 2.0 SD below the mean value for young adults (a T
score lower than –2) and had no more than one vertebral fracture at
screening. The date of onset of menopause was defined as the date of
oophorectomy when applicable or as 12 months after the cessation of menses
in women over 50 years of age and 18 months after the cessation of menses in
women between 45 and 49 years of age. Major criteria for exclusion included
systemic estrogen treatment within the previous three months, evidence of
secondary osteoporosis, clinical or laboratory evidence of hepatic or renal
disease, disorders of the parathyroid or thyroid glands, a serum
25-hydroxyvitamin D concentration of 15 ng per milliliter (37 nmol per
liter) or less, a history of cancer, previous treatment with bisphosphonates
or fluoride, and current therapy with any other drug known to affect the
skeleton. The protocol was approved by the ethics committee at each center,
and all the women gave written informed consent. Thirty-five women withdrew
from the study, most commonly for personal reasons (in the case of 15 women)
or because of adverse events (14 women). Thus, 316 women completed the
study.
Treatment
All women received a calcium supplement (1 g per day). At study entry the
women were randomly assigned to receive one of six treatment regimens in a
double-blind fashion. Three groups received zoledronic acid by intravenous
infusion every three months, one group at a dose of 0.25 mg, one at a dose
of 0.5 mg, and one at a dose of 1 mg. Two other groups received a total dose
of 4 mg of zoledronic acid — one group receiving a single 4-mg infusion at
the beginning of the trial and the other group receiving two doses of 2 mg
each, one at base line and the other at six months. Thus, there were three
groups that received a total dose of 4 mg in one year. The sixth group
received only placebo (saline). To maintain blinding, all women received an
intravenous infusion of either zoledronic acid or placebo every three
months. All infusions were 20 ml in volume and were infused over a period of
five minutes. A dose of 4 mg given in this way produces a mean (±SD) peak
serum concentration of zoledronic acid of 393±100 ng per milliliter.
Infusions were prepared at each center by a pharmacist who had no contact
with the patients and were labeled with the subject's study number and
supplied to the study personnel.
Bone Density Measurement
The bone mineral density of the lumbar spine, the nondominant proximal femur
and forearm, and the total body were measured by dual-energy x-ray
absorptiometry at base line and at 6, 9, and 12 months with the use of
Hologic QDR (Hologic, Waltham, Mass.) or Lunar (Madison, Wis.) instruments.
Data were converted to Hologic-equivalent values by the method of Hui et al.
9 <http://content.nejm.org/cgi/content/full/346/9/#R9>  A central laboratory
(Institut für Funktionsanalyse, Hamburg, Germany) was responsible for the
supervision of quality control for these measurements and notified
investigators if any patient had a decrease in bone density of more than 5
percent from the base-line values.
Markers of Bone Turnover
Measurement of biochemical markers was performed in a central laboratory
with the use of established methods. For serum bone-specific alkaline
phosphatase, the Tandem-MP Ostase assay was used (Hybritech, Liege,
Belgium). Serum osteocalcin was measured with the N-MID one-step
enzyme-linked immunosorbent assay (Osteometer, Herlev, Denmark). Urinary
type I collagen cross-linked N-telopeptide was measured with the Osteomark
assay (Ostex, Seattle). Serum type I collagen C-telopeptide was measured
with the CrossLaps assay (Osteometer).
Statistical Analysis
The necessary sample size was calculated as the number of patients needed to
detect a difference between the zoledronic acid groups and the placebo group
of at least 4 percent in the degree of change in lumbar-spine bone mineral
density from base line to 12 months. Bonferroni's correction was used to
adjust for multiple comparisons in order to ensure an overall nominal
significance level of 0.05. Given a noncentral t distribution with a type I
error of 0.025, a power of 80 percent, a two-sided alternative, and a
standard deviation of 5.7 percent, we calculated that 40 patients were
needed in each treatment group in order to allow detection of a difference
of 4 percent. To allow for a possible 15 percent dropout rate, a total
sample size of 290 was selected.
All analyses were performed according to the intention-to-treat principle
with the use of all available data from all patients who received study
drug. Missing values were not imputed or replaced. Analysis of covariance
was performed (with the Proc Mixed procedure of SAS software [SAS Institute,
Cary, N.C.]) to estimate differences between the treatment groups. The
statistical fixed-effects model considered center and treatment as main
variables. In addition, the base-line values, if measured, were used as
covariates. The analyses were repeated with the last observation carried
forward and produced essentially the same results (data not shown).
For the primary variable, adjustment for multiple comparisons between
placebo and the active doses of zoledronic acid was performed at a one-sided
alpha level of 0.025, according to the method of Marcus et al. 10
<http://content.nejm.org/cgi/content/full/346/9/#R10>  For secondary
variables, pairwise comparisons were investigated in the exploratory
analysis (unadjusted for multiple comparisons). The pairwise comparisons
were tested at a two-sided level of significance of 0.05. In addition to the
P value for the comparisons between treatment groups, estimates of the
differences and associated 95 percent confidence intervals were calculated.
The protocol was designed and developed by the sponsor and submitted to the
investigators for comments and amendments. The final protocol was then
accepted by the investigators and submitted to the ethics review committees
of their institutions for approval. Data management and statistical analysis
were performed by the sponsor. Interpretation of the data and preparation of
the manuscript were performed by a publication committee that included three
academic researchers who were investigators in the trial (Drs. Reid, Brown,
and Burckhardt) and Dr. Trechsel, the author of the study protocol, as a
representative of the sponsor. These authors had full and unfettered access
to the data and take full responsibility for the completeness and accuracy
of the reported data. The study sponsor placed no limits on statements made
in the final paper.
Results
Study Subjects
The base-line characteristics of the women who participated in the study are
summarized in Table 1 <http://content.nejm.org/cgi/content/full/346/9/#T1> .
All but two women were white, and none had vertebral fractures at study
entry.


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Table 1. Base-Line Characteristics.

Bone Mineral Density
Mean bone-mineral-density values in the lumbar spine corresponded to a T
score of –2.9. All groups receiving zoledronic acid regimens had a
progressive increase in bone mineral density in the lumbar spine throughout
the 12-month study period, although the rate of increase tended to slow in
the second half of the study ( Figure 1A
<http://content.nejm.org/cgi/content/full/346/9/#F1> ). Throughout the
study, the values for lumbar-spine bone mineral density achieved with all
zoledronic acid regimens were significantly higher than those in the placebo
group (P<0.001), and there were no significant differences among the
zoledronic acid groups. At 12 months, the mean lumbar-spine bone mineral
density in the groups receiving zoledronic acid was 4.3 to 5.1 percent
higher than the mean value in the placebo group, which remained stable. The
bone mineral density in the femoral neck also increased progressively
throughout the study period; all zoledronic acid groups had similar
increases to values that were significantly higher than those in the placebo
group (differences of 3.1 to 3.5 percent at 12 months, P<0.001) ( Figure 1B
<http://content.nejm.org/cgi/content/full/346/9/#F1> ). The femoral-neck
bone mineral density declined by 0.4 percent in the placebo group.


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Figure 1. Effects of Various Regimens of Zoledronic Acid and Placebo on Bone
Mineral Density in the Lumbar Spine (Panel A) and the Femoral Neck (Panel B)
in Postmenopausal Women with Low Bone Mineral Density.
The curves show the mean changes from base line in the placebo group and the
groups receiving zoledronic acid in four doses of 0.25 mg each, four doses
of 0.5 mg each, four doses of 1 mg each, two doses of 2 mg each, and one
dose of 4 mg. Achieved density with all regimens of zoledronic acid was
significantly higher than that with placebo, and there were no significant
differences among the zoledronic acid groups. I bars represent standard
errors.

Bone mineral density at the distal radius responded to zoledronic acid
treatment to a lesser extent, resulting in differences from the placebo
group of 0.8 to 1.6 percent at 12 months (data not shown); in the placebo
group, distal radial bone mineral density decreased by 0.8 percent. All
zoledronic acid regimens except the four doses of 0.25 mg each resulted in
distal radial bone mineral density that was significantly greater than that
in the placebo group (P<=0.05 for all comparisons). The results for
total-body bone mineral density were similar (data not shown). At 12 months,
the differences in total-body bone mineral density between the zoledronic
acid groups and the placebo group ranged from 0.9 percent to 1.3 percent and
were significant (P<0.03 for all comparisons) for all regimens except the
four doses of 0.5 mg each.
Markers of Bone Turnover
Markers of bone resorption reached a nadir at one month (median decreases of
65 to 83 percent in serum C-telopeptide and 50 to 69 percent in the urinary
N-telopeptide:creatinine ratio), whereas there were no significant changes
in the placebo group ( Figure 2
<http://content.nejm.org/cgi/content/full/346/9/#F2> ). The decrease in
markers of resorption tended to be dose-dependent, particularly at three
months — a pattern that is consistent with previous reports that higher
doses of bisphosphonates increase the duration of action of the drug. 11
<http://content.nejm.org/cgi/content/full/346/9/#R11>  We do not have full
documentation of the immediate reductions in bone resorption after each
infusion, because most samples were obtained only every three months. The
suppression of resorption was maintained at 12 months. At 12 months, the
zoledronic acid regimens were associated with decreases of 49 to 52 percent
in serum C-telopeptide (as compared with a decrease of 8 percent in the
placebo group) and decreases of 54 to 65 percent in the ratio of urinary
N-telopeptide to creatinine (as compared with an increase of 3 percent in
the placebo group). All zoledronic acid groups had values for these markers
of resorption that were significantly different from those in the placebo
group (P<0.01 for all comparisons), but there were no significant
differences among the zoledronic acid groups. Bone-specific alkaline
phosphatase and osteocalcin, which are serum markers of bone formation,
showed similar responses, but there was no sharp decrease apparent at one
month ( Figure 3 <http://content.nejm.org/cgi/content/full/346/9/#F3> ).
Again, suppression persisted at 12 months with all doses (P<0.001).


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Figure 2. Effects of Various Regimens of Zoledronic Acid and Placebo on
Biochemical Markers of Bone Resorption.
The ratio of N-telopeptide of type I collagen (in nanomoles) to creatinine
(in millimoles) was measured in urine (Panel A). C-telopeptide was measured
in serum (Panel B). The curves show the mean changes from base line in the
placebo group and the groups receiving zoledronic acid in four doses of 0.25
mg each, four doses of 0.5 mg each, four doses of 1 mg each, two doses of 2
mg each, and one dose of 4 mg. Beginning at one month, the effects of all
regimens were significantly different from those of placebo. The I bars
represent standard errors.



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Figure 3. Effects of Various Regimens of Zoledronic Acid and Placebo on
Serum Markers of Bone Formation.
The curves show the mean changes from base line in serum osteocalcin (Panel
A) and serum bone-specific alkaline phosphatase (Panel B) in the placebo
group and the groups receiving zoledronic acid in four doses of 0.25 mg
each, four doses of 0.5 mg each, four doses of 1 mg each, two doses of 2 mg
each, and one dose of 4 mg. Beginning at three months, the serum
concentrations with all regimens of zoledronic acid were significantly lower
than base-line values. The I bars represent standard errors.

Bone Biopsies
A 7.5-mm transiliac biopsy specimen was obtained from 43 women and
double-labeled with tetracycline. Of these specimens, 27 were complete and
suitable for histomorphometric analysis. The sections were undecalcified and
stained with Goldner's trichrome, except for tetracycline measurements,
which were made on unstained sections. Women treated with zoledronic acid at
any dose had significantly lower proportions of mineralizing surfaces, rates
of bone formation, adjusted mineral apposition rates, and activation
frequencies than the women in the placebo group (differences of 71 percent
to 84 percent, P<0.05); there were nonsignificant differences in the
proportion of eroded surface (39 percent lower than that in the placebo
group, P<0.06) and in eroded volume (48 percent lower, P<0.07). No change
was noted in cortical bone thickness or porosity; cancellous bone volume;
trabecular thickness, separation, or number; wall width of trabecular bone
packets; number of nodes per volume of tissue; or osteoid maturation time.
No dose effect was found with respect to any of these factors. No evidence
of osteomalacia was found, either by qualitative assessment or on the basis
of such quantitative measures as osteoid thickness and volume or the mineral
apposition rate. No other qualitative abnormalities were apparent.
Fractures
Spinal radiographs at base line and one year showed no vertebral fractures
during the study. No nonvertebral fractures occurred in the group receiving
four doses of 0.25 mg of zoledronic acid; two nonvertebral fractures
occurred in the group receiving four doses of 1 mg of zoledronic acid; and
one nonvertebral fracture occurred in each of the other groups.
Safety
Mean serum calcium concentrations in the zoledronic acid groups declined
significantly (P<0.05 for all comparisons), by approximately 0.08 mmol per
liter, between base line and one month but were similar to those in the
placebo group from three months onward. Serum phosphate concentrations in
the zoledronic acid groups had decreased by 0.06 to 0.12 mmol per liter at
one month and generally remained about 0.05 mmol per liter below those in
the placebo group throughout the study period, although they did not differ
significantly from those in the placebo group at one year. Intact
parathyroid hormone was measured in serum at base line and 12 months. There
were no significant differences among the groups at the 12-month follow-up,
although the mean value was about 30 percent higher than the base-line value
in the women in the group receiving four doses of 1 mg of zoledronic acid,
possibly because sampling was performed only three months after the last
dose had been administered in this group.
The rates of adverse events were similar in all the active-treatment groups
( Table 2 <http://content.nejm.org/cgi/content/full/346/9/#T2> ). However,
treatment-related adverse events were significantly more common in the
zoledronic acid groups than in the placebo group (rates of 45 to 67 percent
vs. 27 percent; data not shown). In the zoledronic acid groups, most adverse
events were instances of musculoskeletal pain, nausea, or fever, most of
which were rated as mild. Most occurred the first time the drug was
administered. Five women withdrew from the study because of drug-related
adverse events, all of which were reactions after the first infusion of
zoledronic acid. These withdrawals were not dose-related; two occurred in
women who were receiving the lowest dose and two in women receiving the
highest dose. There was no evidence of adverse effects on renal function
with any of these regimens. Overall, the proportions of women who withdrew
from the study because of adverse events were similar in all groups.
Symptoms at the infusion site were uncommon in all groups (e.g., reported in
no patients receiving a single 4-mg dose of zoledronic acid and in two
patients receiving placebo). Iritis did not develop in any patients, and the
occurrence of any eye disorder was uncommon (e.g., reported in two patients
receiving a single 4-mg dose of zoledronic acid and in nine patients
receiving placebo).


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Table 2. Adverse Events.

Discussion
Intermittent intravenous administration of the potent bisphosphonate
zoledronic acid results in changes in biochemical markers of bone turnover
and in bone mineral density that are similar to those observed with daily
oral bisphosphonate therapy. Thus, the reductions in markers at one year in
the present study are similar to those seen with 5 mg of risedronate per
day, 12 <http://content.nejm.org/cgi/content/full/346/9/#R12>  2.5 to 5 mg
of ibandronate per day, 13
<http://content.nejm.org/cgi/content/full/346/9/#R13>  and 10 mg of
alendronate per day. 14
<http://content.nejm.org/cgi/content/full/346/9/#R14> , 15
<http://content.nejm.org/cgi/content/full/346/9/#R15> , 16
<http://content.nejm.org/cgi/content/full/346/9/#R16>  Zoledronic acid
increases spinal bone mineral density at 12 months to 5 percent above values
found in patients receiving placebo — an increase similar to that achieved
with a daily 10-mg dose of alendronate (5 percent), 17
<http://content.nejm.org/cgi/content/full/346/9/#R17>  a daily 5-mg dose of
risedronate (3 percent), 12
<http://content.nejm.org/cgi/content/full/346/9/#R12>  or a daily 150-mg
dose of pamidronate (5 percent). 18
<http://content.nejm.org/cgi/content/full/346/9/#R18>  Intravenous
zoledronic acid also produced results similar to those of the oral regimens
at the femoral neck (alendronate, 3 percent increase in bone density;
risedronate, 2 percent; pamidronate, 3 percent) and in the total body
(alendronate, 1.5 percent increase; pamidronate, 1 percent).
Our study assessed longer intervals between doses than have been assessed by
previous studies of intermittent bisphosphonate therapy. Etidronate has been
used for many years in two-week oral courses administered at three-month
intervals. 19 <http://content.nejm.org/cgi/content/full/346/9/#R19> , 20
<http://content.nejm.org/cgi/content/full/346/9/#R20>  There is also
evidence that intravenous pamidronate 3
<http://content.nejm.org/cgi/content/full/346/9/#R3>  or ibandronate, 4
<http://content.nejm.org/cgi/content/full/346/9/#R4>  given every three
months, has beneficial effects on bone density in women with postmenopausal
osteoporosis. The disappointing data on fractures from a recent study of
intermittent ibandronate therapy (1 mg intravenously every three months) 21
<http://content.nejm.org/cgi/content/full/346/9/#R21>  has been interpreted
as indicating that a dosing interval of three months is too long. However,
this ibandronate regimen did not stably suppress markers of bone resorption;
a substantial maximal suppression of C-telopeptide excretion (by 50 percent)
was rapidly offset, so that the level before the next dose was only 10 to 20
percent below that in the placebo group. 4
<http://content.nejm.org/cgi/content/full/346/9/#R4>  As a result, the
changes in bone density (increases of 2.9 percent in the spine at 12 months
4 <http://content.nejm.org/cgi/content/full/346/9/#R4>  or to 4 percent
higher than the spinal bone mineral density in the placebo group at 3 years
21 <http://content.nejm.org/cgi/content/full/346/9/#R21> ) were smaller than
those found in our study; this effect is consistent with the moderate effect
of this dose of ibandronate on the incidence of vertebral fracture (a 26
percent reduction at 3 years). Our data indicate that much longer dosing
intervals are compatible with efficacy (in terms of both suppression of bone
turnover and increase in bone density) if the dose of bisphosphonate is
sufficiently large. Indeed, the present study does not establish a maximal
dosing interval, since turnover remained suppressed at 12 months. Thus, it
is possible that a longer interval between doses could be effective,
particularly if larger doses of zoledronic acid were used.
How a single infusion of zoledronic acid suppresses bone turnover for so
long remains to be determined. Prolonged suppression is not the result of
the persistence of the drug in the circulation, given that by 24 hours after
administration, drug levels are less than 1 percent of the
postadministration peak and 40 percent of the dose has been excreted in the
urine. The balance of the dose is presumably bound to bone and is slowly
released back into the circulation, giving rise to a 167-hour terminal
half-life in plasma. It has been thought that bisphosphonates are located
exclusively on osteoclastic surfaces 22
<http://content.nejm.org/cgi/content/full/346/9/#R22>  and that short-term
exposure inhibits activity in a single generation of basic multicellular
units in bone. The life span of the basic multicellular unit (about three
months) then determines the duration of action of the drug. However,
evidence suggests that bisphosphonates are also deposited on osteoblastic
and resting bone surfaces and remain there for the long term. 23
<http://content.nejm.org/cgi/content/full/346/9/#R23>  The existence of such
deposits would provide a possible explanation for our results, since residue
from a single dose could interfere with the future development of basic
multicellular units at these surfaces. It is also possible that direct
effects on existing basic multicellular units and osteocytes 24
<http://content.nejm.org/cgi/content/full/346/9/#R24> , 25
<http://content.nejm.org/cgi/content/full/346/9/#R25>  result in reduced
formation of succeeding basic multicellular units.
Zoledronic acid was generally well tolerated, and the rate of retention of
subjects in the study was high. The adverse events that were more common in
women receiving zoledronic acid are those that have occurred previously in
patients receiving intravenous aminobisphosphonates and are transient.
Infrequent doses may increase tolerance of these side effects.
The inclusion of a placebo group in this study permits quantification of the
size of the therapeutic effect and facilitates comparison of the present
data with those from other studies. We believe this use of a placebo is
ethical, since the bone density used as a criterion for entry (a T score of
less than –2) is higher than that required at the participating centers for
a diagnosis of osteoporosis and would certainly not be considered to be a
threshold for therapeutic intervention at these centers. Thus, the study was
conducted in a low-risk population — a characterization supported by the
fact that no spinal fractures occurred during the study period. Only one
sixth of these low-risk subjects received placebo, and they received it for
a maximum of 12 months, after which all women received active therapy.
Osteoporosis has been regarded as requiring daily therapy, and maintaining
compliance with daily regimens for a predominantly asymptomatic condition
has been a major problem. 26
<http://content.nejm.org/cgi/content/full/346/9/#R26> , 27
<http://content.nejm.org/cgi/content/full/346/9/#R27>  Administration of
treatment at intervals of 6 to 12 months or more is likely to be much more
acceptable to patients and could reduce costs. A greater proportion of the
at-risk population might take advantage of prophylaxis against osteoporosis
if an intermittent regimen were used, and the rate of fractures might
therefore decrease. However, studies that demonstrate an effect on the rate
of fractures are needed before any recommendation can be made.
Supported by a grant from Novartis Pharma.
We are indebted to Esther Hagin of Novartis Pharma, Basel, Switzerland, for
her expert work in conducting the trial.

Source Information
From the Department of Medicine, University of Auckland, Auckland, New
Zealand (I.R.R.); the Centre de Recherche du Centre Hospitalier del
Université Laval, Quebec, Que., Canada (J.P.B.); the Centre Hospitalier
Universitaire Vaudois, Lausanne, Switzerland (P.B.); Novartis
Pharmaceuticals, East Hanover, N.J. (Z.H., P.R.); Novartis Pharma, Basel,
Switzerland (U.T., A.W.); the Department of Rheumatology, Université
Catholique de Louvain, St. Luc, Brussels, Belgium (J.-P.D.); the Department
of Endocrinology, University Hospital of Ghent, Ghent, Belgium (J.-M.K.);
the Medizinische Universitätspoliklinik, Inselspital Bern, Bern, Switzerland
(P.J.); the Endocrinology and Supportive Care Clinic, Institut J. Bordet,
Free University of Brussels, Brussels, Belgium (J.-J.B.); and the Department
of Rheumatology and Bone Diseases, Hôpital Edouard Herriot, Lyons, France
(P.J.M.).

Other authors were Maria Luisa Brandi, M.D., Unità di Endocrinologia,
Ospedale di Careggi, Florence, Italy; Johann Broell, M.D., Medizinische
Abteilung mit Rheumatologie und Osteologie, Kaiser-Franz-Josef-Spital der
Stadt Wien, Vienna, Austria; Raffaele Di Micco, M.D., Centro di
Fisiopatologia della Menopausa, Ospedale Maggiore La Maternità, Bologna,
Italy; Andrea Riccardo Genazzani, M.D., Ospedali Riuniti S. Chiara, Pisa,
Italy; Dieter Felsenberg, M.D., Universitätsklinikum Benjamin Franklin,
Strahlenklinik und Poliklinik, Berlin, Germany; Joachim Happ, M.D.,
Frankfurt, Germany; Michael J. Hooper, F.R.A.C.P., Department of
Endocrinology, Concord Hospital, Concord, N.S.W., Australia; Jochen Ittner,
M.D., Augsburg, Germany; Georg Leb, M.D., Klinische Abteilung für
Endokrinologie und Nuklearmedizin, Medizinische Universitätsklinik, Graz,
Austria; Hans Mallmin, M.D., Ph.D., Medicinkliniken, Akademisca Sjukhuset,
Uppsala, Sweden; Timothy Murray, M.D., Metabolic Bone Clinic, St. Michael's
Hospital, Toronto; Sergio Ortolani, M.D., Centro Studi Metabolismo Osseo,
Istituto Auxologico Italiano, Milan, Italy; Alessandro Rubinacci, M.D.,
Unità Metabolica dell'Osso, Ospedale S. Raffaele, Milan, Italy; Maria Sääf,
M.D., Ph.D., Endokrinologiska Kliniken, Karolinska Sjukhuset, Stockholm,
Sweden; Goran Samsioe, M.D., Ph.D., Kvinnokliniken, Universitetskliniken,
Lund, Sweden; and Leon Verbruggen, M.D., Ph.D., Department of Rheumatology,
Academic Hospital, Brussels Free University, Brussels, Belgium.
Address reprint requests to Professor Reid at the Department of Medicine,
University of Auckland, Private Bag 92019, Auckland, New Zealand, or at
[log in to unmask] <mailto:[log in to unmask]> .
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Edward E. Rylander, M.D.
Diplomat American Board of Family Practice.
Diplomat American Board of Palliative Medicine.